In systemic lupus erythematosus (SLE), progressive immune dysregulation results in the production of autoantibodies that lead to the injury of multiple end organs and severe disease. Currently, standard therapy for lupus patients involves non-specific immune suppression, which has undesirable side effects. Therefore, there is great interest in gaining insights into new mechanisms that may result in novel, disease-specific treatments. Though SLE is antibody-mediated, the primary mechanism(s) of disease is not thoroughly understood. In the lyn-/- model of murine lupus, emerging evidence suggests that a hyperresponsive myeloid compartment may play a substantial role in autoimmune disease. We aim to confirm and extend studies characterizing the hyperresponsive effector mechanisms of lyn-/- macrophages. We will evaluate effector mechanisms that might contribute to increased B cell differentiation and plasma cell survival such as IL-6 secretion and BAFF expression. We also propose to establish whether lupus pathogenesis is dependent on lyn-/- myeloid cell presence by generating B- and myeloid- specific conditional knockout mice and analyzing B, myeloid, and autoimmune phenotypes.